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Potassium in severe diabetic ketoacidosis
APRIL
The
American
Journal
1973
of Medicine VOLUME
54
NUMBER
4
EDITORIAL
Potassium in Severe Diabetic Ketoacidosis
PAUL M. BEIGELMAN, Los Angeles,
M.D
California
Departments of Medicine and Pharmacology, USC School of Medicine, and Department of Medicine, Los Angeles County-USC Medical Center, Los Angeles, California. Requests for reprints should be addressed to Dr. Paul M. Beigelman, Department of Medicine, University of Southern California School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033. Manuscript received August 23, 1972; revision accepted November 3, 1972.
The primary mechanisms causing profound depletion of total body potassium in diabetic ketoacidosis have been thoroughly investigated and include loss of intracellular protein and water, acidosis and osmotic diuresis [l-3]. Despite the low total body potassium, severe hyperkalemia may be associated with diabetic ketoacidosis resulting from a deficit of body fluid, mainly caused by osmotic diuresis, and diminished renal function. As therapy is begun, serum potassium declines, sometimes precipitously, due to continued urinary loss of potassium, dilution of extracellular fluid, correction of acidosis and administered insulin causing re-entry of potassium into the cells. Profound hyper- or hypokalemia, even if transient, may be dangerous or prove fatal. Major alterations in potassium flux across nerve and muscle cell membranes, reflecting changes in ratio of extracellular to intracellular potassium, alter electrical activity of these tissues which may lead to fatal changes in cardiovascular function or cause respiratory arrest. In 340 sequential episodes of severe diabetic ketoacidosis recently reported from this institution [4], the serum potassium levels on admission were usually normal or high. Low values, occurred in only 4 per (cent of the less than 3.5 meq/liter, cases. These patients required significantly greater amounts of parenteral potassium. A statistically significant inverse relationship between the serum potassium level on admission (mean 5.3, range 2.1 to 8.4 meq/liter) and total potassium infused (mean 170, range 0 to 620 meq) confirmed this observation. The enormous variability of potassium requirements observed, 0 to 620 meq, merits close attention. None of the 32 fatalities in this series could be directly attributed to potassium aberrations. Mean serum potassium levels on admission did not differ significantly in elderly subjects (over 50 years) with nonfatal and fatal episodes. In contrast,
April 1973
The American Journal of Medicine
Volume 54
419
POTASSIUM
IN SEVERE
DIABETIC
KETOACIDOSIS-BEIGELMAN
Correlation of Eight-Hour Change in Serum TABLE I Potassium with Changes in Serum Glucose, and with Insulin, Bicarbonate and Potassium Therapy Mean ZII SEM* Change of serum potassium liter)
rt
(meq/ -1.4
f
0.1 +0.352
Change of serum glucose
(mg/lOO cc)
Change of serum potassium liter)
-440f24
(meq/ -1.5
* 0.1 +0.419
Potassium
therapy
(meq)$
Change of serum potassium liter)
125 f
5
(meq/ -1.4
f
0.1 -0.256
Insulin
therapy
450 * 25
(units)$
Change of serum potassium liter
(meq/ -1.4
+ 0.1 -0.309
Bicarbonate
therapy
135i 10
(meq)j
* Standard error of mean. t Correlation coefficient between serum and serum glucose change or therapy. $ To nearest 5 meq or 5 units.
potassium
change
serum glucose and urea nitrogen levels on admission were significantly higher in patients with fatal episodes. Mean serum potassium levels were identical (5.1 meq/liter) in young patients (under 30 years) and in elderly patients (over 50). Both groups received approximately the same amount of parenteral potassium. These studies also confirmed the impression that the most significant decline of serum potassium occurred shortly after “coma” therapy was begun. The lowest values were observed one hour after therapy was instituted, with little or no further change occurring in the subsequent one to three hours. In some instances, this was simply a
reflection of adequate potassium repletion begun shortly after admission. The greater the elevation of the serum potassium level on entry, the more profound its subsequent decrease. To some extent, this was a consequence of diminished or delayed potassium repletion. The decline in serum potassium eight hours after admission, in approximately 130 episodes, showed a statistically significant association with the decrease in serum glucose and with amounts of insulin and bicarbonate infused (Table I). Not unexpectedly, decline of serum potassium was inversely proportional to the dose of potassium. There was no significant association with the amount of glucose infused in eight hours. Solar et al. [6], utilizing balance studies, recently presented further evidence supporting the key role of aggressive potassium therapy in severe diabetic ketoacidosis. They reported quite high potassium requirements, from 225 to 343 meq. Their balance studies also demonstrated the definite need for larger amounts ot potassium when bicarbonate was administered. The influence of therapy upon serum potassium levels in severe ketoacidosis is evidently profound and further emphasizes the importance of careful monitoring, primarily with frequent serum potassium determinations although serial electrocardiograms are helpful. In earlier reports, the potassium
deficit
was
estimated
as approximately
5 meq/
[2,3,6]. More recent studies indicate that in some cases there may be a more profound deficit, as much as 10 meq/kg, requiring larger quantities of parenteral potassium for repletion [7-121. The need for carefully monitored, vigorous parenteral potassium replacement therapy, perhaps in considerable excess of usually recommended doses, is reemphasized when the physician is confrdnted with a case of severe diabetic ketoacidosis. kg
in
severe
diabetic
ketoacidosis
REFERENCES 1.
2.
3.
4.
5.
420
Atchley W, Loeb RF, Richard W Jr, Benedict M, Driscoll E: On diabetic acidosis. A detailed study of electrolyte balances following the withdrawal and re-establishment of insulin therapy. J Clin Invest 12: 297, 1933. Martin H, Wertman M: Serum potassium, magnesium, and calcium levels in diabetic acidosis. J Clin Invest 26: 217, 1947. Burnell JH. Villamil MF, Uyeno TB, Scribner BH: The effect in humans of extracellular pH changes on the relationship between serum potassium concentration and intracellular potassium. J Clin Invest 35: 935, 1956. Beigelman PM: Severe diabetic ketoacidosis (diabetic “coma”): 482 episodes in 257 patients; experience of three years. Diabetes 20: 490, 1971. Solar NG, Bennet MA, Dixon K, Fitzgerald MG, Malins JM: Potassium balance during treatment of diabetic ketoacidosis with special reference to the use of bi-
April 1973
The American
Journal of Medicine
6.
7.
8. 9. 10. 11. 12.
Volume 54
carbonate. Lancet 2: 665, 1972. Nabarro JDH, Spencer AG, Stower JM: Metabolic studies in severe diabetic ketosis. Quart J Med 21: 225, 1952. Seftel HC, Kew MC: Early and intensive potassium replacement in diabetic acidosis. Diabetes 15: 694, 1966. Pullen H, Doig A, Lambie AT: Intensive intravenous potassium or replacement therapy. Lancet 2: 809, 1967. Abramson E, Arky R: Diabetic acidosis and initial hypokalemia. JAMA 196: 401, 1966. Clementsen HJ: Potassium therapy. A break with tradition. Lancet 2: 175, 1962. Bergen S: Extreme hypokalemia during treatment of diabetic acidosis. New York J Med 67: 2267, 1967. Beigelman PM, Martin HE, Miller LV, Grant WJ: Severe diabetic ketoacidosis. JAMA 210: 1082, 1969.
The
American
Journal
1973
of Medicine VOLUME
54
NUMBER
4
EDITORIAL
Potassium in Severe Diabetic Ketoacidosis
PAUL M. BEIGELMAN, Los Angeles,
M.D
California
Departments of Medicine and Pharmacology, USC School of Medicine, and Department of Medicine, Los Angeles County-USC Medical Center, Los Angeles, California. Requests for reprints should be addressed to Dr. Paul M. Beigelman, Department of Medicine, University of Southern California School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033. Manuscript received August 23, 1972; revision accepted November 3, 1972.
The primary mechanisms causing profound depletion of total body potassium in diabetic ketoacidosis have been thoroughly investigated and include loss of intracellular protein and water, acidosis and osmotic diuresis [l-3]. Despite the low total body potassium, severe hyperkalemia may be associated with diabetic ketoacidosis resulting from a deficit of body fluid, mainly caused by osmotic diuresis, and diminished renal function. As therapy is begun, serum potassium declines, sometimes precipitously, due to continued urinary loss of potassium, dilution of extracellular fluid, correction of acidosis and administered insulin causing re-entry of potassium into the cells. Profound hyper- or hypokalemia, even if transient, may be dangerous or prove fatal. Major alterations in potassium flux across nerve and muscle cell membranes, reflecting changes in ratio of extracellular to intracellular potassium, alter electrical activity of these tissues which may lead to fatal changes in cardiovascular function or cause respiratory arrest. In 340 sequential episodes of severe diabetic ketoacidosis recently reported from this institution [4], the serum potassium levels on admission were usually normal or high. Low values, occurred in only 4 per (cent of the less than 3.5 meq/liter, cases. These patients required significantly greater amounts of parenteral potassium. A statistically significant inverse relationship between the serum potassium level on admission (mean 5.3, range 2.1 to 8.4 meq/liter) and total potassium infused (mean 170, range 0 to 620 meq) confirmed this observation. The enormous variability of potassium requirements observed, 0 to 620 meq, merits close attention. None of the 32 fatalities in this series could be directly attributed to potassium aberrations. Mean serum potassium levels on admission did not differ significantly in elderly subjects (over 50 years) with nonfatal and fatal episodes. In contrast,
April 1973
The American Journal of Medicine
Volume 54
419
POTASSIUM
IN SEVERE
DIABETIC
KETOACIDOSIS-BEIGELMAN
Correlation of Eight-Hour Change in Serum TABLE I Potassium with Changes in Serum Glucose, and with Insulin, Bicarbonate and Potassium Therapy Mean ZII SEM* Change of serum potassium liter)
rt
(meq/ -1.4
f
0.1 +0.352
Change of serum glucose
(mg/lOO cc)
Change of serum potassium liter)
-440f24
(meq/ -1.5
* 0.1 +0.419
Potassium
therapy
(meq)$
Change of serum potassium liter)
125 f
5
(meq/ -1.4
f
0.1 -0.256
Insulin
therapy
450 * 25
(units)$
Change of serum potassium liter
(meq/ -1.4
+ 0.1 -0.309
Bicarbonate
therapy
135i 10
(meq)j
* Standard error of mean. t Correlation coefficient between serum and serum glucose change or therapy. $ To nearest 5 meq or 5 units.
potassium
change
serum glucose and urea nitrogen levels on admission were significantly higher in patients with fatal episodes. Mean serum potassium levels were identical (5.1 meq/liter) in young patients (under 30 years) and in elderly patients (over 50). Both groups received approximately the same amount of parenteral potassium. These studies also confirmed the impression that the most significant decline of serum potassium occurred shortly after “coma” therapy was begun. The lowest values were observed one hour after therapy was instituted, with little or no further change occurring in the subsequent one to three hours. In some instances, this was simply a
reflection of adequate potassium repletion begun shortly after admission. The greater the elevation of the serum potassium level on entry, the more profound its subsequent decrease. To some extent, this was a consequence of diminished or delayed potassium repletion. The decline in serum potassium eight hours after admission, in approximately 130 episodes, showed a statistically significant association with the decrease in serum glucose and with amounts of insulin and bicarbonate infused (Table I). Not unexpectedly, decline of serum potassium was inversely proportional to the dose of potassium. There was no significant association with the amount of glucose infused in eight hours. Solar et al. [6], utilizing balance studies, recently presented further evidence supporting the key role of aggressive potassium therapy in severe diabetic ketoacidosis. They reported quite high potassium requirements, from 225 to 343 meq. Their balance studies also demonstrated the definite need for larger amounts ot potassium when bicarbonate was administered. The influence of therapy upon serum potassium levels in severe ketoacidosis is evidently profound and further emphasizes the importance of careful monitoring, primarily with frequent serum potassium determinations although serial electrocardiograms are helpful. In earlier reports, the potassium
deficit
was
estimated
as approximately
5 meq/
[2,3,6]. More recent studies indicate that in some cases there may be a more profound deficit, as much as 10 meq/kg, requiring larger quantities of parenteral potassium for repletion [7-121. The need for carefully monitored, vigorous parenteral potassium replacement therapy, perhaps in considerable excess of usually recommended doses, is reemphasized when the physician is confrdnted with a case of severe diabetic ketoacidosis. kg
in
severe
diabetic
ketoacidosis
REFERENCES 1.
2.
3.
4.
5.
420
Atchley W, Loeb RF, Richard W Jr, Benedict M, Driscoll E: On diabetic acidosis. A detailed study of electrolyte balances following the withdrawal and re-establishment of insulin therapy. J Clin Invest 12: 297, 1933. Martin H, Wertman M: Serum potassium, magnesium, and calcium levels in diabetic acidosis. J Clin Invest 26: 217, 1947. Burnell JH. Villamil MF, Uyeno TB, Scribner BH: The effect in humans of extracellular pH changes on the relationship between serum potassium concentration and intracellular potassium. J Clin Invest 35: 935, 1956. Beigelman PM: Severe diabetic ketoacidosis (diabetic “coma”): 482 episodes in 257 patients; experience of three years. Diabetes 20: 490, 1971. Solar NG, Bennet MA, Dixon K, Fitzgerald MG, Malins JM: Potassium balance during treatment of diabetic ketoacidosis with special reference to the use of bi-
April 1973
The American
Journal of Medicine
6.
7.
8. 9. 10. 11. 12.
Volume 54
carbonate. Lancet 2: 665, 1972. Nabarro JDH, Spencer AG, Stower JM: Metabolic studies in severe diabetic ketosis. Quart J Med 21: 225, 1952. Seftel HC, Kew MC: Early and intensive potassium replacement in diabetic acidosis. Diabetes 15: 694, 1966. Pullen H, Doig A, Lambie AT: Intensive intravenous potassium or replacement therapy. Lancet 2: 809, 1967. Abramson E, Arky R: Diabetic acidosis and initial hypokalemia. JAMA 196: 401, 1966. Clementsen HJ: Potassium therapy. A break with tradition. Lancet 2: 175, 1962. Bergen S: Extreme hypokalemia during treatment of diabetic acidosis. New York J Med 67: 2267, 1967. Beigelman PM, Martin HE, Miller LV, Grant WJ: Severe diabetic ketoacidosis. JAMA 210: 1082, 1969.